CHL Attenuates MIA-Induced Osteoarthritis by Regulating Inflammatory, Catabolic, and Anabolic Pathways Associated with Cartilage and Subchondral Bone Degeneration.

Background/Objectives: Osteoarthritis (OA) is characterized by cartilage degeneration, extracellular matrix (ECM) disruption, inflammation, and impaired joint function. A standardized phytosterol-rich avocado/soybean unsaponifiable preparation (CHL) was examined in monosodium iodoacetate (MIA)-induced OA in Sprague-Dawley rats. Methods: Rats were orally administered low-, medium-, or high-dose CHL for 2 weeks before and 4 weeks after MIA induction. Results: CHL attenuated MIA-induced weight-bearing deficits and structural joint abnormalities. CHL also reduced cartilage degradation markers, including cartilage oligomeric matrix proteins and the C-terminal crosslinked telopeptide of type II collagen. CHL alleviated systemic inflammation by reducing serum interleukin-6, tumor necrosis factor-α, and prostaglandin E2 levels. Furthermore, CHL decreased the serum levels of matrix metalloproteinases (MMP)-1, MMP-2, MMP-9, and MMP-13, indicating reduced matrix-degrading responses. In joint cartilage tissues, CHL suppressed the mRNA expression of pro-inflammatory mediators and catabolic genes, such as Mmp1, Mmp3, and Mmp9. Additionally, CHL modulated cartilage anabolism and ECM-related markers by reducing collagen type I alpha 1 chain expression and enhancing SRY-box transcription factor 9, tissue inhibitor of metalloproteinase 1, and collagen type II alpha 1 chain expression. High-resolution liquid chromatography-mass spectrometry profiling of CHL revealed several tentatively identified compounds, such as (+)-discodermolide, epicoccamide, and brasilicardin C. Conclusions: Overall, these findings indicate that CHL may attenuate MIA-induced OA-associated functional impairment, structural alterations, inflammation, and cartilage matrix degradation, with medium doses showing the strongest protective effects. However, because CHL administration was initiated before OA induction, these findings primarily reflect preventive/protective effects and may not directly represent the therapeutic efficacy of CHL in established OA.